Flow boiling heat transfer is investigated in a single silicon microchannel with microstructured sidewalls using R134a (at 0.19 reduced pressure) and HFE-7000 (at 0.035 reduced pressure) as working fluids. The channel is 51 mm long with a 400 μm x 400 μm square cross section. Sidewall microstructures in the form of triangular cavities for the entire height of the channel were introduced during the fabrication process. By including the cavity pattern in the photolithography mask design, high accuracy and reproducibility is ensured during the fabrication of the test sample. A smooth channel with the same geometry but without sidewall microstructures was also fabricated. Flow boiling experimental results are presented for both channel configurations. For R134a at mass velocity G = 800 kg m−2 s−1, the comparison of the boiling curves shows that: in the channel with the microstructures, the wall superheat at the onset of nucleate boiling (ONB) is reduced from 21 K to 6 K as compared to the smooth channel. An increase of the flow boiling heat transfer coefficient up to 40% is found in the microstructured channel, which must be due to the increased number of active nucleation sites. Heat transfer results, flow visualizations and comparison between R134a and HFE-7000 data provide a clearly evidence of the active role of bubble nucleation during flow boiling in microchannels. These results are of fundamental importance in the design of next generation thermal management systems for electronics.